J . Org. Chem. 1988,53, 42-45
42
Synthesis of Vinca Alkaloids and Related Compounds. 37.' Some New Reactions of (&)-C-Norquebrachamineand Its Derivatives Gyorgy Kalaus,t Numan Malkieh,t MBria KajtBr-Peredy,t JBnos Brlik,t Lajos Szabb,t and Csaba SzBntay** Department of Organic Chemistry and M S Laboratory of the Institute for General and Analytical Chemistry, Technical University, Budapest, Gell6rt t6r 4, H-1521 Budapest, Hungary, and Central Research Institute for Chemistry, Hungarian Academy of Sciences, Budapest, Pusztaszeri u t 59-67, H-1525 Budapest, Hungary Received April 23, 1987
Oxidation of (f)-C-norquebrachamine(2) with chromyl acetate (Cr03/ (CH,CO),O) in dichloromethane/acetic acid resulted, by ring cleavage, in the macrocyclic compound 17. Similar oxidation of 3 and 4 gave 7 + 8 and 16b, respectively. Scheme I Previously we have reported2 that the mesylate obtained from la-ethyl-l~-(hydroxymethyl)-1,2,3,4,6,7,12,12baCH,SO,octahydroindolo[2,3-~]quinolizine immediately formed a quaternary salt (1). The behavior of 1 toward nucleophiles was investigated, and it was established that with hydride ion (A)-C-norquebrachamine (2) was obtained exclusively; with cyanide ion both in protic and in dipolar aprotic solvents, (f)-3a-cyano-C-norquebrachamine (3) proved to be the main product (Scheme I). In the present paper we describe further transformations of these compounds. A t first we wished to transform the cyano group of 3 into a methoxycarbonyl function in order to obtain (A)-C-norvincadine and/or its C3 epimer.3 In CH30H/HC14or in CH30H/H,S02, 3 remained unchanged, while treatment with KOH in ethylene glyc01~?~ resulted in no definite product. However, on boiling of 3 in KOH/EtOH for Scheme I1 several days, two products were isolated. The main product was the amide 4, which resisted further hydrolysis in acidic medium. As a minor product, (f)-3-oxo-C-norquebrachamine (6) was separated. Compound 6 was presumably formed via 5 , which can be derived from 3 as a result of oxidation by air (Scheme 11). This latter obI I servation prompted us to study the behavior of the ring I system on oxidation. When 3 was reacted with common I oxidizing agents (such as Hg(AcO)2sand KMn0:) or the 1I Polonovsky reactionlo was applied, either no reaction was observed or undefined products were formed. Oxidation - HCN with chromyl acetatell was, however, successful. Compound 3 was dissolved in a mixture of CH2C12and AcOH and then oxidized with a solution of CrOs in Ac20 at -60 HO CN to -30 "C. As reaction products, 7 and 8 were obtained. 6 5 It is worth mentioning that higher temperature and longer reaction time favors the formation of 8 (Scheme 111). Scheme I11 Structures 7 and 8 were inferred from NMR observations. The absence of the indole NH signal in the proton spectrum of 7, on the one hand, and the number as well as the chemical shift values of the sp2 carbon resonances, on the other, indicated that this product contained an indolenine moiety. An additional quaternary sp3 carbon resonance 7 lcro. / at 84.18 ppm was assignable to C13b substituted by a 7. (CHSCO)20 hydroxyl group. The carbon-13 spectrum of 8 indicated CHgCIz the presence of two carbonyl functions in the molecule CHsCOOH (206.58 and 162.92 ppm); their location (C4 and C13) within the product followed from the chemical shift changes of neighboring carbon atoms. The (&)-C-norrhazidigeninel2derivative 7 proved to be the intermediate of 8. Compound 8 was obtained by 8 starting from 7 under the mentioned reaction conditions. Similar observations have also been reported by Japanese tives. In order to convert the cyano group of 7 into an ester authors13 on oxidation of 2,3-disubstituted indole derivafunction, it was dissolved in MeOH/HCl and kept at room /
L :
-
Technical University, Budapest.
* Hungarian Academy of Sciences, Budapest.
(1) Part 36: Kalaus, Gy.; Galambos, J.; Kajtir-Peredy, M.; Tamis, J.; Szab6, L.; Sipi, J.; Szlntay, Cs. Liebigs Ann. Chem. 1987, 745.
0022-3263/88/ 1953-0042$01.50/0 0 1988 American Chemical Society
J. Org. Chem., Vol. 53, No. 1, 1988 43
Synthesis of Vinca Alkaloids and Related Compounds
20.91-. ,
Scheme IV
& -
E2H5
H
EN
10
7
11
17
12
tCH30H lHCl CH3
I
c=o I
THFIroom temperature pyridinelA
0 *C
14 110 13
CN K2C03
12 13
Figure 1. 13C chemical shifts of 7, 11, 16b, 8, 17, 12, and 13, 6 (ppm). * may be interchanged. Scheme V 2
I
13
CH3 15
temperature. After about 0.5 h, the starting material disappeared, and a well-defined product (10) was formed, presumably by elimination-addition14 via 9 (Scheme IV). 18a, R = H b, RzCONH,
(2) Kalaus, Gy.; Malkieh, N.; Katona, I.; Kajtar-Peredy, M.; Koritshszky, T.; K h a n , A.; SzaM, L.; Szbtay, Cs. J. Org. Chem. 1985, 50, 3760. (3) Zsadon, B.; Tam&, J. Chem. Ind. (London) 1972, 32. (4) Atta-Ur-Rahman; Beilser, J. A.; Harley-Masson, J. Tetrahedron 1980,36, 1063. (5) Kalaus, Gy.; Szab6, L.; GyBry, P.; Szentirmay, E.; Szhtay, Cs. Acta Chim.Acad. Sci. Hung. 1979,101, 387. (6) Kutney, J. P.; Chan, K. K.; Failli, A.; Formson, J. M.; Gletsos, C.; 1968, 90, 3891. Nelson, V. R. J. Am. Chem. SOC. (7) Kutney, J. P.; Chan, K. K.; Failli, A.; Formson, J. M.; Gletsos, C.; Leutwiler, A.; Nelson, V. R.; de Souza, J. P. H e h . Chim.Acta 1975,58, 1648. (8) Kutney, J. P.; Brown, R. T.; Piers, E.; Hadfield, J. R. J.Am. Chem. SOC. 1970, 92, 1708. (9) Bycroft, B. W.; Schumann, D.; Patel, M. B.; Schmid, H. Helu. Chim. Acta 1964, 47,1147. (10) Kalaus, Gy.; Kiss, M.; Kajtfu-Peredy, M.; Brlik, J.; Szab6, L.; Szintay, Cs. Heterocycles 1985, 23, 2783. (11) (a) Jovanovics, K. U.S.Patent 3899493; Chem. Abstr. 1975, 83, 1793605. (b) Jovanovics, K. U.S. Patent 4 310 582; Chem. Abstr. 1982,96, 181492n. (12) (a) Kny, H.; Witkop, B. J. Org. Chem. 1960,25, 635. (b) Markey, S.;Biemann, K.; Witkop, B. Tetrahedron Lett. 1967, 157. (13) Hino, T.;Yamaguchi, H.; Matsuki, K.; Nakano, K.; Sodeoka, M.; Nakagawa, M. J. Chem. SOC.,Perkin Trans. 1 1983,141 and references cited therein.
17
The lH and 13C NMR data of the product 10 attested to the presence of an indole moiety. The occurrence of a three-proton singlet a t 3.55 ppm and a carbon resonance a t 56.93 ppm disclosed the presence of a methoxyl group in the molecule. The position of this substituent followed from the replacement of the C10 methylene signal of 3 (26.46 ppm) by a methine carbon resonance (77.68 ppm) in the spectrum of 10. The hydroxyl group of the tertiary alcohol in 7 was acylated in pyridine with Ac20, and the product (1 1) was easily desacylated by CH30H/NaOCH,. On prolonged treatment of 7 with pyridine, 12 was formed, likely through the tautomeric intermediate (7a)by proton abstraction from OH and subsequent ring opening. Reduction of 12 with NaBH4 yielded 13. The C=N double bond of indolenine 7 can be reduced by LiAlH, at room temperature to the hydroxyindoline 14. The latter can be dehydrated to 3 either by MeOH/HCl or by boiling in (14) Incze, M.; %ti, F.; Kardos-Balogh, 2s.; Kajtlr-Peredy, M.; Szhtay, Cs. Heterocycles 1985, 23, 671.
44 J. Org. Chem., Vol. 53, No. 1, 1988 pyridine. Acetylation of 14 furnished 15. The chromyl acetate oxidation was performed on compounds 2 and 4 as well (Scheme V). Compound 17 was obtained b y starting from 2, presumably t h r o u g h intermediate 16a, while 4 furnished 16b (Figure 1).
Experimental Section General Procedures. The IR spectra were measured with a Spectromom 2000 spectrophotometer. The 'H and I3C NMR spectra were recorded on a Varian XL-100 Fourier transform spectrometer operating a t 100.1 and 25.16 MHz, respectively. Chemical shifts (in parts per million) are relative to internal Me&. Mass spectra were determined by using a JEOL-JMS-01-SG-2 instrument. All melting points are uncorrected. Thin-layer chromatography separations were carried out on silica gel (Kieselgel 60 PF254+366),developed by C,H,-MeOH, 10:1.4, and eluted by CH2Clz-MeOH, 1O:l. The organic layers were dried over MgSO.,. 3a-Carbamoyl-C(4)-norquebrachamine(5a) (4) a n d 3Oxo-C(4)-norquebrachamine(5a)(6). A solution of 3' (1.5 g, 5.1 mmol) and KOH (11.5 g, 205 mmol) in EtOH (200 mL) was stirred a t reflux for 6 days. The solvent was removed under reduced pressure, and the residue was diluted with H 2 0 (70 mL) and then extracted with CH2C12(100 mL). The organic layer was dried and evaporated in vacuo. The residue was treated with cold MeOH (10 mL) to give 4 (0.91 g, 57.2%): mp 215-218 "C (CH,CN-EtOH); IR (KBr) u 3350 (indole NH), 1660 cm-' (amide C=O); MS, m / z (relative intensity) 311 (39), 267 (3), 181 (19), 125 (50),124 (loo), 110 (26), 96 (35); 'H NMR (CDCl, + DMSO-$, 2:l) 6 0.69 (3 H, t, J = 7.5 Hz, CH,CH,), 4.60 (1H, S, C3-H), 6.2 and 6.7 (2 H, br s, CONH2), 6.95-7.55 (4 H, m, Ar), 9.90 (1 H, br s, NH); I3C NMR (CDC1, DMSO-d,, 1:l) 6 7.98 (CZO), 17.85 (C6), 25.56 (ClO), 28.60 (C19), 31.95 (C5), 39.91 (C4), 44.85 (C3), 50.80* (C9), 51.40* (C7), 53.95 (C18), 109.94 ( C l l ) , 111.03 (ClS), 117.15 (C13), 118.26 (C14), 120.30 (C15), 127.72 (C12), 131.46 (C2), 134.44 (C17), 173.82 (CONH2) [* may be interchanged]. Anal. Calcd (found) for CI9Hz5N30:C, 73.28 (73.14); H, 8.09 (7.99); N, 13.49 (13.26). The mother liquor was concentrated and then separated by TLC. The faster running fraction was evaporated and crystallized from MeOH to give 6 (0.16 g, 11.1%) as white crystals: mp 258-262 "C (MeOH); IR (KBr) Y 1645 cm-' (C=O); MS, m / z (relative intensity) 282 (45), 254 (22), 225 ( l l ) , 199 (31), 143 (69), 124 (loo),112 (25), 110 (24); 'H NMR (CDCl,) 6 0.74 (3 H, t, J = 7.4 Hz, CHZCHJ, 2.78 (1 H, d, J A B = 15 Hz, C18HAHB),3.97 (1 H, dd, C ~ ~ - H A H 7.05-7.70 B), (4 H, m, Ar), 8.51 (1H, br s, NH); I3C NMR (DMSO-$ + CDCl,, 2:l) 6 7.24 (C20), 16.24 (C6), 24.42 (ClO), 30.79 (C19), 32.86 (C5), 48.28 (C4), 50.74* (C9), 51.74* (C7), 53.28 (C18), 111.94 ((2161, 119.21 ( C l l ) , 119.31 (C13), 119.54 (C14), 123.79 (C15), 127.14 (ClZ), 131.78 (C2), 135.87 (C17), 203.21 (C=O) [* may be interchanged]. Oxidation of 3. A solution of 3 (1.00 g, 3.40 mmol) in CH2C12 (100 d) and AcOH (50 mL) was cooled to -70 "C, and then CrO, (1.0 g, 10.0 mmol) in Ac20 (100 mL) was added in small portions at -60 "C. The reaction mixture was stirred at -60 to -30 "C for 2 h and then poured into a mixture of concentrated NH,OH (400 mL) and ice (400 g). The organic layer was separated, and the inorganic part was extracted with CH2ClZ(400 mL). The combined extracts were dried and evaporated in vacuo, and the residue was treated with MeOH to afford 7 (0.55 g, 52.2%): mp 212-214 "C (EtOH); IR (KBr) u 2300 (CN), 1590 cm-' (indolenine C=N); UV (CH,OH) A,, (log c) 223 (4.4349), 266 (3.7905), 284 nm (3.7557);MS, m / z (relative intensity) 309 (loo), 292 (35), 280 (8), 125 (64), 124 (40), 110 (69), 96 (22); 'H NMR (CDCl,) 6 0.91 (3 H, t, J = 7.5 Hz, CH2CH3),4.67 (1 H, s, C8-H), 7.0-7.5 (4 H, m, Ar); I3C NMR (DMSO-$ + CDCl,, 2:l) see Figure 1. The mother liquor was concentrated and then separated by TLC to afford 7 (0.10 g, 9.5%) and 8 (30 mg, 2.7%) as white crystals: mp 198-200 "C (MeOH); IR (KBr) v 3300 (indole NH), 2300 (CN), 1688 cm-' (C=O); MS, m / z (relative intensity) 325 (loo), 296 (15), 165 (16), 164 (16), 147 (721, 146 (521, 135 (401, 124 (511, 123 (24), 120 (14), 92 (11); 'H NMR (CDCl,) 6 0.98 (3 H, t, J = 7.5 Hz, CH,CH,), 1.2-2.6 (10 H, m), 2.9-3.5 (4 H, m), 4.20 (1 H, s, C12-H), 7.15 (1 H, ddd, BJ = 6.4 + 7.5 + 1.0 Hz, C2c-H), 7.22 (1 H, ddd, ZJ = 7.5 + 2.8 + 0.6 Hz, CPd-H), 7.46 (1H, ddd, ZJ = 8.2 + 6.4 + 2.8 Hz, C2b-H), 8.28 (1 H, ddd, TJ = 8.2 + 1.0 + 0.6 Hz. C2a-H),
+
Kalaus et ai. 9.76 (1H, br s, NH); I3C NMR (CDC1, + DMSO-$, 2:l) see Figure 1.
F u r t h e r Oxidation of 7. CrO, (0.10 g, 1.0 mmol) in AczO (10 mL) was added to a solution of 7 (100mg, 0.32 mmol) in a mixture of CH2C1, (20 mL) and AcOH (5 mL). The reaction mixture was stirred a t room temperature for 24 h and then treated with concentrated NH,OH a t 0 "C. The organic layer was separated, and the inorganic part was extracted with CH2Clz(40 mL). The combined extracts were dried and evaporated, and the residue was separated by TLC to afford 8 (10 mg, 9.5%). 3a-Cyano-lO-methoxy-C(4)-norquebrachamine(5a)(10). Compound 7 (0.55 g, 1.78 mmol) was dissolved in MeOH (60 mL) saturated with HC1 a t 0 "C. The solution was allowed to stand a t 0 "C for 1.5 h, then treated with concentrated NH,OH, and extracted with CH2C12(100 mL). The organic layer was dried and evaporated in vacuo. The residue was separated by TLC to give 10 (0.27 g, 47%) as white crystals: change in modification 180-200 "C; mp 206-210 "C (MeOH); IR (KBr) v 3350 (indole NH), 2320 cm-' (CN); MS, m / z (relative intensity) 323 (25), 292 (6), 198 (5), 125 (loo), 110 (50), 96 (33); 'H NMr (CDC1,) 6 0.79 (3 H, t, J = 7.5 Hz, CHZCH,), 2.60 (1 H, d, J A B = 14 Hz, C18HAHB), 2.70 (1 H, d, C18-HAHB),3.00 (2 H, m, C7-H,), 3.27 (2 H, m, C9-H2),3.55 (3 H, s, OCH,), 4.61 (1 H, dd, CJ = 10 Hz, C10-H), 4.85 (1 H, s, C3-H), 7.0-7.8 (4 H, m, Ar), 8.31 (1 H, br S, NH); I3C NMR (CDC13) 6 7.82 (CHZCH,), 18.88 (C6), 29.15 (CH2CH3),31.33 (C5), 35.76 (C3), 41.01 (C4), 51.33 (Ci), 53.33 (Cia), 54.11 (C9), 56.93 (OCH,), 77.68 (ClO), 110.94 (C16), 114.61 ( C l l ) , 118.63 (CN), 120.41* (C13), 120.44* (C14), 122.62 (C15), 125.04 (ClZ), 127.32 (C2), 135.30 (C17) [* may be interchanged]. C, 74.27 (74.18);H, 7.79 (7.57); Anal. Calcd (found) for C&,N,O: N, 12.99 (13.26). 13b-Acetoxy-8a-cyano-7oc-ethyl-3,7-methano1,2,4,5,6,7,8,13b-octahydroazecino[5,4-b]indole (11). Compound 7 (0.30 g, 0.97 mmol) was dissolved in a mixture of pyridine (15 mL) and Ac,O (1mL). The reaction mixture was refluxed for 1.5 h, and then the solvent was removed in vacuo (0.5 mbar) at room temperature. The residue was treated with 5% NaHCO, to give 11 (0.23 g, 76.5%) as white crystals: mp 143-145 "C (MeOH); IR (KBr) u 2320 (CN), 1755 (C=O), 1590 cm-' (indolenine C=N); MS, m / z (relative intensity) 351 (81), 308 (50), 292 (77), 291 (42), 262 (291, 125 (loo), 124 (721, 110 (55), 96 (26); 'H NMR (CDCl,) 6 0.97 (3 H, t, J = 7.5 Hz, CH2CH3),2.09 (3 H, s, CH,COO), 4.61 (1H, s, C8-H), 7.1-7.7 (4H, m, Ar); I3C NMR (CDCl,) see Figure 1. Desacetylation of 11. A solution of 1 1 (65 mg, 0.18 mmol) in MeOH (6 mL) was added to MeONa (22 mg, 0.4 mmol) in MeOH (10 mL). The reaction mixture was refluxed for 5 min, then poured into water, and extracted with CH2C12.The organic layer was dried and evaporated in vacuo. The residue was crystallized from MeOH to give 7 (45 mg, 78.6%). Preparation of 12. A solution of 7 (0.20 g, 0.65 mmol) in pyridine (15 mL) was refluxed for 8 days and then evaporated in vacuo. The remaining oil was purified by TLC to afford 12 (0.11 g, 55%) as white crystals: mp 173-174 "C (MeOH); IR (KBr) u 2240 (CN), 1704-1612 cm-' (C=O, C=C); UV (CH,OH) A,, (log e ) 217 (4.5249), 260 (4.2817), 311 nm (4.5992); MS, m / z (relative intensity) 309 (loo), 294 (9), 280 (321, 252 (16), 237 (13), 146 (41), 135 (7), 120 (111,77 (18), 70 (20); 'H NMR (CDCl,) 6 0.93 (3 H, t, J = 7.5 Hz, CHZCH,), 1.93 (1H, d, Jg,, = 12.5 Hz, C14-HA),3.45 (2 H, m, C6-Hz),3.46 (1 H, d, C14-HB),6.90 (1H, dd, J = 7.7, 7.1, and 1.1 Hz, C2c-H), 7.03 (1H, ddd, J = 8.1, 1.1, and 0.5 Hz, C2a-H), 7.30 (1 H, ddd, J = 7.7, 1.9, and 0.5 Hz, C2d-H), 7.39 (1 H, ddd, J = 8.1, 7.1, and 1.9 Hz, C2b-H), 7.53 (1H, d, J = 10.2 Hz, C13-H), 13.38 (1H, br d, J = 10.2 Hz, NH); 13C NMR (CDCI,) see Figure 1. Selective Reduction of 12. A solution of 12 (0.17 g, 0.55mmol) in EtOH (17 mL) was cooled to 0 "C, and then NaBH, (0.17 g, 4.5 mmol) was added in small portions. The reaction mixture was stirred at G 5 "C for 40 min, then poured into water (30 mL), and extracted with CHzCl,. The organic layer was dried and evaporated to afford 13 (0.15 g, 87.7%) as white crystals: mp 167-169 "C (MeOH); IR (KBr) u 3400 (OH), 1645 (C=C), 2210 cm-' (CN); MS, m / z (relative intensity) 312 (481, 311 (loo),296 (lo), 298 (30), 161 (lo), 146 (13), 135 ( l l ) , 130 (25), 124 (l5), 110 ( l l ) , 96 (15), 77 (22), 72 (341, 71 (191, 58 (191, 44 (43),42 (37);'H NMR (CDC1,) 6 0.84 (3 H, t, J = 7.2 Hz, CH,CHJ, 1.90 (1 H, d,
J. Org.
45
Chem. 1988, 53, 45-49
Jgem-= 12.2 Hz, C14-HA),3.22 (1H, d, C14-HB),4.73 (1H, br dd, ZJ - 7 Hz, C4-H), 6.89 (1H, m, C2a-H), 6.93 (1H, m, C2c-H), 7.20 (1H, m, C2b-H), 7.45 (1H, d, J = 10.4 Hz, C13-H), 7.50 (1 H, m, C2d-H), 12.02 (1H, br d, J = 10.4 Hz, NH); 13C NMR (CDCl,) see Figure 1. Reduction of 7. A solution of 7 (0.50 g, 1.62 mmol) in T H F (30 mL) was dropped to a suspension of LiAlH4(0.50 g, 13.2 "01) in T H F (20 mL) within 20 min. The reaction mixture was stirred a t room temperature for 10 min, then cooled, and decomposed with 10% NaOH (5 mL). The organic layer was separated, and the inorganic part was extracted with T H F (30 mL). The combined extracts were dried and evaporated in vacuo. The residue was treated with EgO to give 14 (0.32 g, 63.6%) as white powder: mp 195-198 "C dec; IR (KBr) u 3280-3200 (OH, indole NH), 2300 cm-' (CN); MS, m/z (relative intensity) 311 (loo), 294 (29), 293 (42), 282 (13), 264 (29), 250 (24), 177 (40), 163 (42), 147 (37), 144 (17), 124 (59), 110 (35), 96 (46); 'H NMR (CDC1, + DMSO-d,, 2:l) 6 0.91 (3 H, t, J = 7.3 Hz, CH,CH,), 4.32 (1H, br s, C8a-H), 4.78 (1H, br s, NH), 6.5-7.3 (4 H, m, Ar); 13C NMR (DMSO-d, CDC13, 3:l) 6 7.63 (CHZCH,), 46.38 (C2), 50.92 (C4 + C14), 122.61 (C13), 128.60 ( C l l ) , 149.20 (C9a). Dehydration of 14. (a) A solution of 14 (30 mg, 0.10 mmol) in pyridine (6 mL) was refluxed for 6 h and then evaporated in vacuo. The remaining oil was crystallized from MeOH to give 3 (26 mg, 92.0%). (b) Compound 14 (100 mg, 0.32 mmol) was dissolved in MeOH (15 mL) saturated with HC1 a t 0 "C. The solution was allowed to stand at 0 "C for 30 min, then treated with 25% NH40H, and extracted with CHzC1,. The organic layer was dried and evaporated in vacuo. The residue was crystallized from MeOH to give 3 (90 mg, 95.5%). Selective Acetylation of 14. To a solution of 14 (0.18 g, 0.58 "01) in T H F (25 mL) were added anhydrous KzCO3 (0.7 g) and AczO (0.5 mL). The reaction mixture was stirred a t reflux for 75 min, then cooled to room temperature, and filtered. The filtrate was evaporated, and the residue was treated with 5% NaHC0, to give 15 (0.11 g, 53.8%) as white powder: mp 208-210 "C (MeOH); IR (KBr) v 3270 (OH), 2300 (CN), 1640 cm-' (amide ( 2 4 ) ; MS, m/z (relative intensity) 353 (loo), 338 (85), 337 (25), 336 (24), 293 (16), 264 (21), 250 (22), 117 (38), 164 (35), 130 (26), 110 (38), 96 (52); 'H NMR (CDCl,) 6 0.85 (3 H, t, J = 7.3 Hz, CHZCH,), 2.37 (3 H, s,COCH3), 3.34 (2 H,s, C8-H + OH), 5.47 (1 H, br s, C8a-H), 7.0-7.45 (4 H, m, Ar); 13C NMR (CDCl,) 6 7.15 (CHZCH,), 21.98 (C5), 23.99 (COCH,), 28.68 (CHZCH,), 31.84 (C1 + C6), 40.54 (C7),42.00 (C8), 46.33 (C2), 50.94* (C4), 51.50* (C14),
+
71.97 (C8a),77.33 (C13b), 115.24 (ClO), 118.45 (CN), 123.41' (C12), 124.47' (C13), 130.01 (Cll), 137.60 (C13a), 140.58 (Cga), 168.73 (COCH,) [*st may be interchanged]. Oxidation of 2. CrO, (0.2 g, 2.0 mmol) in Ac,O (20 mL) was dropped to a solution of 2' (200 mg, 0.74 mmol) in a mixture of CHZClz(40 mL) and AcOH (10 mL). The reaction mixture was stirred a t room temperature for 3 h, then treated with concentrated NH40H (80 mL) at 0 "C, and extracted with CHzCl, (100 mL). The organic layer was dried and evaporated in vacuo. The remaining oil was purified by TLC to afford 17 (25 mg, 11.2%) as white crystals: mp 150-151 "C (MeOH); IR (KBr) u 1690-1680 cm-' (C=O); MS, m/z (relative intensity) 300 (loo), 285 (12), 271 (4), 243 (7), 147 (15), 146 (18), 138 (8), 124 (44), 123 (55), 110 (16); 'H NMR (CDCl,) 6 0.94 (3 H, t, J = 7.5 Hz, CH,CH,), 2.13 (1 H, d, J A B = 13 Hz, C~B-HAHB), 2.76 (1H, d, C~B-HAHB), 7.06 (1 H, ddd, Z J = 7.5 7.0 + 1.0 Hz, C ~ C - H )7.18 , (1H, ddd, Z J =
+
7.5+2.1+0.6H~,C2d-H),7.41(1H,ddd,ZJ=8.1+7.0+2.1 Hz, C2b-H), 8.26 (1H, ddd, Z J = 8.1 + 1.0 + 0.6 Hz, C2a-H), 9.81 (1 H, br s, NH); 13C NMR (CDCl,) see Figure 1. Oxidation of 4. A solution of CrO, (0.10 g, 1.0 mmol) in AczO (10 mL) was dropped to a solution of 4 (100 mg, 0.32 mmol) in a mixture of CHzC1, (20 mL) and AcOH (5 mL). The reaction mixture was stirred a t room temperature for 1 h, then treated with concentrated NHIOH (40 mL) at 0 "C, and extracted with CHzClz(100 mL). The organic layer was dried and evaporated in vacuo. The remaining oil was crystallized from MeOH to give 16b (18 mg, 17.1%) as white powder: mp 219-222 "C dec; IR (KBr) u 3300 (OH), 1645 cm-' (amide C=O); MS, m/z (relative intensity) 327 (loo),310 (75), 283 (23), 251 (64), 125 (66), 124 (59), 110 (46); 'H NMR (DMSO-d6 CDCl,, 2:l) 6 0.86 (3 H, t, J = 7 Hz,CH2CH3),4.30 (1H, s, C&H), 6.3 and 7.7 (2 H, br s, CONHJ, 7.1-7.5 (4 H, m, Ar);13CNMR (DMSO-d, CDCl,, 31) see Figure 1.
+
+
Acknowledgment. W e express our sincere thanks t o Dr. PBter Gyory, Anna Korcsog-Kassa, and Magdolna T6th for their valuable help. T h e financial support of t h e Richter Gedeon Pharmaceutical Co. and the Hungarian Academy of Sciences is gratefully acknowledged. Registry No. (*)-2, 97720-63-3; (*)-3, 97720-62-2; (*)-4, 111324-81-3;(*)-6,111324-82-4; 7,111324-83-5; (&)-8,111324-84-6; 10, 111324-85-7; 11, 111324-86-8; (f)-12, 111324-87-9; 13, 111324-88-0; 14, 111324-89-1; 15, 111324-90-4; 16b, 111324-91-5; (*)-17, 111324-92-6.
Efficient Conjugate Alkylation of a,@-UnsaturatedNitro Olefins by Triorganoalanes Angelo Pecunioso*t and Rita Menicaglit7t Dipartimento di Chimica e Chimica Industriale and Centro di Studio del CNR per le Macromolecole Stereordinate ed Otticamente Attive, 56100 Pisa, Italy Received April 2, 1987 Both trialkylaluminum (AlR,; R = Et, i-Bu) and triorganoaluminum etherates (AlR,.OEh; R = Et, i-Bu, Ph) rapidly react with a,&unsaturated nitro olefins to give only 1,4--monoaUylatedproducts in high yield. The natures of substrates, the reaction conditions as well as the reagents molar ratio, do not cause significant variations on the recovered products. Reactions involving nitro compounds in carbon-carbon bond-forming processes are of increasing importance owing to the remarkable versatility of t h e nitro group.' Dipartimento di Chimica e Chimica Industriale.
* Centro di Studio del CNR per le Macromolecole Stereordinate
ed Otticamente Attive.
0022-3263/88/1953-0045$01.50/0
Scheme I
a - N i t r o olefins are unique synthetic intermediates2 because a wide class of nucleophiles adds, in a Michael-type 0 1988 American Chemical Society
